The overall objective of this proposal is to investigate the impact of CRACC upregulation on CD4+ and CD8+ T cells of HAART-treated HIV-1-infected patients and develop a novel CRACC-targeting immunotherapeutic strategy aimed to restore T cell functions in HIV-1 patients. HAART for the treatment of HIV-1 infection sustains viral suppression and increases CD4 count, however, it fails to completely control viral replication and reservoirs as well as CD4+ T cell recovery in 10-25% of HIV-1 patients, indicating a critical need for the development of novel therapies that control HIV-1 viral replication and eliminate persistent viruses. Vaccine efforts to combat HIV-1 infection have been limited in efficacy, as such there is not a vaccine approved for use against HIV-1 to date. It has been proposed that blockade of T cell immune checkpoints in HIV-1 patients may restore the regulatory and effector functions of HIV-1-specific T cells; however recent data indicate the need for utilizing novel combinatorial strategies to completely control HIV-1 virus. The proposed innovative strategy utilizes a novel immune modulatory protein that targets a unique signaling pathway in T cells. This approach focuses on stimulating HIV-1-specific T proliferation and cytokine production by modulating the inhibitory activity of the CD2-like receptor activating cytotoxic cells (CRACC) receptor in T cells of HIV-1- infected patients. As a result, enhanced reactivation of latent HIV-1 in CD4+ T cells may occur, thus result in better control of HIV-1 virus. We found in our preliminary data a strong inverse correlation between CRACC expression on CD4+ and CD8+ T cells and CD4+ T cells recovery in HAART-treated HIV-1 infected patients. In addition, in a manner similar to activating other T cell inhibitory receptors, activating CRACC signaling in T cells inhibited T cell degranulation. Furthermore, in an in vivo translation approach, we found that co-administration of a murine CRACC-targeting Fc fusion protein (mCRACC-Fc) and HIV-1/Gag-expressing vaccine improved the magnitude and the breadth of vaccine-induced HIV-1/Gag-specific T cell immune responses. Achievement of this project's goals will increase our understanding about HIV-1- associated immune dysregulation and will lead to efficacious new therapies for HIV-1 that can be translated to clinical applications. Finally, successful development of this immunotherapeutic could also establish a new line of investigation about a potential role for CRACC signaling in other chronic inflammatory conditions, including various infectious diseases and cancers.